A NEW APPROACH TO THE DESIGN OF SIGMA-2-SELECTIVE LIGANDS - SYNTHESISAND EVALUATION OF THYL]-N-METHYL-2(1-PYRROLIDINYL)ETHYLAMINE-RELATED POLYAMINES AT SIGMA-1 AND SIGMA-2 RECEPTOR SUBTYPES

A series of polyamines based on the high affinity sigma receptor ligan d henyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) were develope d and evaluated for their binding characteristics at sigma-1 and sigma -2 receptor subtypes. The data indicated that a considerable degree of structural variation is possible while still retaining nanomolar affi nity at a receptors; As the structure of the polyamines was varied, th eir binding at sigma-1 and sigma-2 subtypes showed quite different and in some cases opposite trends, supporting the belief that these are p harmacologically distinct entities. Polyamines containing two nitrogen atoms showed optimal binding at both sigma-1 and sigma-2 receptor sub types. Although additional nitrogen atoms resulted in decreased affini ty at sigma-1 and sigma-2 subtypes, an increase in selectivity for sig ma-2 subtypes was evident; the parent 3 showed greater selectivity for sigma-1 subtypes. Internitrogen spacings had a large effect on bindin g affinity and subtype selectivity. For example, the difference betwee n -(3,4-dichlorobenzyl)-N,N'-dimethylethylenediamine (8) [K-i = 29.9 n M at sigma-1 receptor and 18.3 nM at alpha-2 receptor] to ]-N'-(3,4-di chlorobenzyl)-N/N'-dimethylethylenedi- amine (10) [K-i = 1.49 nM at si gma-1 receptor and 12.1 nM at sigma-2 receptor] illustrates the import ance of internitrogen spacing. Triamines 11 and 13 [K-i(sigma-2)/K-i(s igma-1) = 0.19 and 0.10, respectively] containing the N-N-N-Ar spacing s 3-3-2 and 4-4-2, proved to be the most sigma-2 subtype selective of the 15 polyamines examined in this study. The N-N-N spacings appear to be an important factor in their sigma-2 subtype selectivity. These co mpounds will serve as templates in the design of still further sigma-2 subtype selective ligands. The pyrrolidine ring (present in most of t he polyamines tested in this series) proved to be an important recogni tion site for a receptor binding activity. Furthermore, alkyl substitu tion also appears to be important since the stripped down polyamines N -[2-(3,4-dichlorophenyl)ethyl]ethylenediamine (15) and N-1-[2-(3,4-dic hlorophenyl)ethyl] diethylenetriamine (16) exhibited relatively low bi nding affinity.